5-Azacytidine, 4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one, a compound having the chemical structure,
is an antineoplastic drug exhibiting activity against, e.g., leukemia, lymphoma and various solid tumours. 5-Azacytidine acts also as an inhibitor of DNA methyltransferase and was approved for the treatment of myelodispactic syndromes, a family of bone-marrow disorders. It is being marketed under the name Vidaza by Pharmion.
Crystallization of 5-azacytidine providing a methanol solvate of 5-azacytidine and crystallization of 5-azacytidine hydrate were described by Pískala and {hacek over (S)}orm (Nucleic acid chemistry, Improved and new synthetic procedures, methods and techniques, Part one, L. B. Townsend and R. S. Tipson, Eds., Wiley Inc., New York, 1978, pp. 435-441).
U.S. Pat. No. 6,943,249 (“'249”) claims in claim 1 preparation of form I by recrystallization of 5-azacytidine from a solvent mixture comprising at least one primary solvent and at least one co-solvent selected from the group consisting C2-C5 alcohols, aliphatic ketones, and alkyl cyanides, by cooling said solvent mixture from a temperature selected to allow said 5-azacytidine to dissolve completely to about ambient temperature, and isolating the recrystallized 5-azacytidine. The US '249 patent also claims in claim 11 a method for preparing Form I comprising recrystallizing 5-azacytidine from a solvent mixture comprising at least one primary solvent and at least one co-solvent selected from the group consisting C3-C5 alcohols and alkyl cyanides, by cooling said solvent mixture from a temperature selected to allow said 5-azacytidine to dissolve completely to about −20° C., and isolating the recrystallized 5-azacytidine″ also leads to form I of 5-azacytidine. All of the examples of the '249 patent use DMSO as a solvent to which a co-solvent is added. The '249 patent also describes form I having the most prominent 2 theta angles at 12.182, 13.024, 14.399, 16.470, 18.627, 19.049, 20.182, 21.329, 23.033, 23.872, 26.863, 27.1735, 29.277, 29.591, 30.369, and 32.072.
U.S. Pat. No. 6,887,855 discloses eight polymorphic forms of 5-azacytidine, denominated Forms I-VIII, for which Forms I-III are reported to be in the prior art. The characterization of each of these forms in U.S. Pat. No. 6,887,855 is incorporated herein by reference.
U.S. Pat. No. 6,887,855 (“'855”) discloses the synthesis and isolation of Form I, where the obtained form I is reported to be characterized by the same most prominent two theta angles as described in the '249 patent and by FIG. 1. The '855 patent discloses also a mixture of 5-azacytidine form I and a form identified by the most prominent two theta angles at 13.5, 17.6, and 22.3 degrees two-theta, denominated form II.
U.S. Pat. No. 6,887,855 also reports additional crystalline forms of 5-azacytidine, denominated Form IV having the most prominent 2 theta angles at 5.704, 11.571, 12.563, 14.070, 15.943, 16.993, 18.066, 20.377, 20.729, 21.484, 21.803, 22.452, 22.709, 23.646, 24.068, 25.346, 25.346, 26.900, 27.991, 28.527, 28.723, 30.124, 30.673, 31.059, 35.059, 38.195 and 38.403; Form V having the most prominent 2 theta angles at 11.018, 12.351, 13.176, 13.747, 14.548, 15.542, 16.556, 17.978, 18.549, 19.202, 19.819, 20.329, 21.518, 21.970, 22.521, 23.179, 24.018, 24.569, 27.224, 28.469, 29.041, 29.429, 30.924, 31.133 and 37.938; Form VI, a mixture of form I and a crystalline form which exhibits distinctive peaks at 5.8, 11.5, 12.8, 22.4, and 26.6 degrees two-theta, denominated Form VII; a crystalline form having the most prominent two theta angles at 6.599, 10.660, 12.600, 13.358, 15.849, 17.275, 20.243, 20.851, 21.770, 22.649, 25.554, 25.740, 29.293, 32.148, 35.074, and 38.306 degrees two-theta, denominated Form VIII; as well as an amorphous form, processes for preparation thereof, and conversion of form I to the crystalline form having most prominent diffractions on PXRD at two theta values at 6.566, 11.983, 13.089, 15.138, 17.446, 20.762, 21.049, 22.776, 24.363, 25.743, 26.305, 28.741, 31.393, 32.806, 33.043, 33.536, 36.371, 39.157, and 41.643 degrees two-theta, denominated Form III, and to amorphous form.
According to U.S. Pat. No. 7,078,518 (a divisional of the '855 patent), 5-azacytidine Forms IV, V, VI, and mixtures of form I and VII, are prepared by recrystallization processes that include dissolving 5-azacytidine in dimethylsulfoxide, and at least one co solvent is added to the solution of 5-azacytidine facilitating the crystallization; wherein the co solvents is toluene, methanol or chloroform.
The present invention relates to the solid-state physical properties of 5-azacytidine as well as to processes for preparation thereof.
These properties can be influenced by controlling the conditions under which 5-azacytidine is obtained in solid form. Solid-state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid-state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid-state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance that can be identified unequivocally by X-ray spectroscopy. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by solid-state 13C NMR spectrometry and infrared spectroscopy.
The present invention also relates to solvates of 5-azacytidine. When a substance crystallizes out of solution, it may trap molecules of solvent at regular intervals in the crystal lattice. Solvation also affects utilitarian physical properties of the solid-state like flowability and dissolution rate.
One of the most important physical properties of a pharmaceutical compound, which can form polymorphs or solvates, is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient. Other important properties relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.